Histidine decarboxylase knockout mice, an animal model of a rare genetic form of Tourette syndrome

Histamine modulation of basal ganglia information processing

Microglial abnormalities in animal models of Toruette syndrome

Glutamate Dysregulation in OCD: an MRS Study

Functional and structural connectomics in OCD and Tourette syndrome

Neurofeedback targeting the orbitofrontal cortex for the treatment of OCD

Biological and phenomenological predictors of treatment response in OCD

The genetics of OCD

Research Summary

My research is aimed towards a better understanding of a particular network of brain structures, called the basal ganglia, and the consequences of dysfunction of this network in various neuropsychiatric diseases. The basal ganglia are involved both in motor control and in the formation of habits. Abnormalities in this circuit are implicated in a variety of conditions characterized by maladaptive, inflexible behaviors - habits gone bad. These include obsessive-compulsive disorder, Tourette syndrome, and drug addiction.

Our research in the laboratory has two strands. First, we seek to better understand the mechanisms of normal basal ganglia-dependent habit-like learning, by manipulating this circuit in mice and then testing their ability to learn a variety of tasks. Second, we seek to better understand how perturbation of the basal ganglia system can lead to symptoms of psychiatric disease. We do this by recapitulating some of the biology of diseases such as Tourette syndrome, again in mice, and observing the behavioral and neurophysiological consequences.

I also direct the Yale OCD Research Clinic, where our research aims towards the better understanding of the biology of obsessive compulsive disorder and the development of new treatments. We have a number of active research programs. We are investigating abnormalities in the neurotransmitter glutamate in OCD and whehter glutamate modularing medications can be of therapeutic benefit. We are probling the network connectivity of the brain in OCD and Tourette syndrome using recent advances in fMRI imaging. We are exploring the phenomenological heterogeneity of OCD, seeking clues to how we might better personalize effective treatments. We are also developing innovative neurofeedback techniques, in which patients actually learn to control the activity of key brain regions, in an effort to develop a new type of nonpharmacological treatment.

Extensive Research Description

STUDIES OF BASAL
GANGLIA FUNCTION IN MICE. The basal ganglia, consisting of the
striatum (caudate-putamen) and related subcortical structures, have
historically been considered to have primarily motor functions; but it has
become increasingly clear that they are also involved in a variety of cognitive
and affective processes. Disruption of normal basal ganglia function is
seen in a variety of neuropsychiatric conditions, such as obsessive-compulsive
disorder, Tourette syndrome, and drug addiction. The striatum has been divided into distinct functional
regions, though both the anatomical subdivisions and the functions with which
they are associated remain approximate and subject to debate. The ventral
striatum, consisting of the nucleus accumbens and related structures, has a
well-documented role in reward and reward-driven learning, and has been
extensively researched in the context of drug addiction. The dorsal
striatum (caudate and putamen, in primates) is thought to have a role in the
formation of motor and cognitive patterns and in forms of implicit learning,
including the formation of habits. The Pittenger laboratory is focused on the better
understanding of the mechanisms of dorsal striatum-dependent habit-like
learning, and of the consequences of its perturbation in various
neuropsychiatric conditions. We conduct our researches primarily in mice,
which allows us to take advantage of sophisticated reverse genetic techniques
to perturb the striatal circuitry in molecularly precise ways and to target
specific striatal subregions and neuronal subtypes.

DEVELOPMENT OF NOVEL
BEHAVIORAL ASSAYS. A challenge in this line of work is that
striatum-dependent learning processes have been less studied than those
depending on other brain regions, such as hippocampus, cerebellum, and
amygdala, and have barely been studied in mice at all prior to the last few
years. A major thrust of our efforts has therefore been the establishment
and validation of behavioral assays of striatal function in mice.

CREB IN
STRIATAL SYNAPTIC PLASTICITY AND STRIATUM-DEPENDENT LEARNING. Dr.
Pittenger’s initial work in this direction began during his Ph.D. studies with
recent Nobel Prize winner Eric Kandel, with the production of transgenic mice
expressing a dominant-negative mutant of the ubiquitous transcription factor
CREB specifically in the striatum. CREB has long been known to have a
conserved role in the establishment of long-lasting plasticity; for example,
Dr. Pittenger’s earlier thesis work confirmed its role in the hippocampus in
the stabilization of spatial learning (Pittenger et al, Neuron, 2002). However, the role of CREB-regulated processes in dorsal
striatum-dependent habit-like learning had not previously been directly
studied. We found that inhibition of CREB function in the dorsal striatum
disrupts cortico-striatal synaptic plasticity and several striatum-dependent
learning tasks (Pittenger et al, J Neurosci, 2006). This study
represented the first time that the detailed mechanisms of striatum-dependent
learning had been examined using genetic tools in mice. It also
established a new paradigm (adapted from earlier work in rats) for the analysis
of such learning processes in mice, laying the methodological groundwork for
further analyses.

COMPETITIVE INTERACTIONS
BETWEEN LEARNING SYSTEMS. More recent behavioral work in the
Pittenger laboratory has examined the interaction of dorsal striatum-dependent
learning with other types of learning and other circuits in the brain. We
developed a novel cued water maze task for mice (again taking previous work in
rats as our starting point), and found that the animals could learn to navigate
using distinct strategies driven by either local or spatial cues. Lesions
of the dorsal striatum disrupted cue-driven search, while lesions of the dorsal
hippocampus disrupted spatial navigation. The remarkable finding came
when we looked at interactions: hippocampal lesions not only left cued learning
intact, they enhanced it. Conversely, striatal lesions not only left
spatial learning unimpaired, they made it better. The same effect was see
in our transgenic mice, in which striatal CREB is inhibited and corticostriatal
plasticity is impaired: these animals have impaired cued learning but enhanced
spatial learning (Lee et al, PNAS, 2008). This study was the first to document this sort of
bi-directional enhancement after discrete brain lesions. We interpret the
counter-intuitive results in terms of the multiple memory systems theory of
learning. This theory posits that the mammalian brain contains several
different learning systems, adapted for different types of environmental
contingencies. For example, the hippocampus is adapted for the processing
of spatial or relational information, while the dorsal striatum is hypothesized
to be adapted for the gradual acquisition of discrete cue associations.
Under normal circumstances they are activated in parallel; with training,
whichever system is best able to master the relevant environmental contingency
(e.g. to predict reward) comes to dominate. But in circumstances where
two systems produce disparate behavioral outcomes they can destructively
interfere with one another, or ‘compete’; this is particularly likely early in
training, before differential reinforcement has led to the predominance of one
system. We interpret the enhancement of the function subserved by one
system after manipulations of the other as evidence for the alleviation of such
competition.

STRIATAL
SUBREGIONS. Our ongoing work in this direction seeks to refine our
understanding of the structures underlying cued and spatial learning and their
interaction. The dorsal striatum is not a homogeneous structure;
different areas receive projections from functionally distinct regions of
cortex and are therefore likely to process different sorts of
information. In particular, the dorsolateral striatum (the putamen, in
primates) receives projections from primary sensory and motor cortices, and
therefore is likely to be involved in acquisition of cue-driven learning such
as that we are seeing in the water maze task. The dorsomedial striatum,
in contrast, receives input from association cortices and may have a more
general role. Indeed, studies in rats suggest such a dissociation, and
our own preliminary data suggest that restricted lesions of the dorsomedial
striatum have very different effects from larger disruptions of the whole
dorsal striatum. We are addressing the question of functional
dissociation within the dorsal striatum in several ways. First, we seek
to better define what is meant by the ‘dorsomedial striatum’ and ‘dorsolateral
striatum’ in this context by examining striatal activation by water maze
learning in an unbiased way; we have found the different tasks to produce
distinct patterns of striatal activation, enen though they share all sensory,
motor, and motivational characteristics. Second, we are targeting lesions
to putative striatal subregions and examining the behavioral
consequences. Finally, we are targeting disruptions of CREB-mediated
transcription to striatal subregions using recombinant adeno-associated viruses
(rAAV), to see whether disruption in a restricted subregion is sufficient to
recapitulate the effects we see when CREB is inhibited throughout the dorsal
striatum in our transgenic mice.

NEW METHODOLOGIES FOR
PROBING AND PERTURBING STRIATAL FUNCTION. This latter project
highlights another theme in the Pittenger laboratory’s research portfolio, the
development of novel tools for precise manipulation of specific mechanisms and
cell populations in the dorsal striatum, and in other neural circuits.
The production of transgenic mice allowed restriction of a molecular
manipulation to the dorsal striatum, but it does not suffice for more specific
targeting of manipulations to discrete subregions. For that purpose we
are now using engineered rAAV vectors to deliver our CREB dominant negative
construct, and other gene products, into defined brain areas by stereotaxic
surgery. A first-generation vector, which we are currently using, allows
expression of a CREB dominant negative in target brain regions of varying
size. A second-generation vector, which is under development and working
well in vitro, permits the temporal regulation of the delivered gene, such that
it can be turned on and off; this will allow behavioral experimental designs
not possible with static manipulations, such as dissociating learning from
recall. Another major effort in the laboratory is the targeting of
defined striatal cell populations. The striatum, like any other brain
region or structure, is not homogenous; it is made up of distinct populations
of principal cells and a number of different classes of interneurons.
Different cell types are likely to make different contributions to striatal
function, and perturbation of one or another cell type may result in discrete
behavioral abnormalities or (in humans) patterns of psychopathology. We
have developed a method, combining recombinant viruses with transgenic technologies,
to perturb defined cell populations, without disrupting similar cells elsewhere
in the brain or neighboring cells of different types.

MODELING
PSYCHIATRIC DISEASE. We are applying this technology to model
neuropsychiatric conditions affecting the striatum, especially Tourette
syndrome. This represents a third focus of the laboratory. Modeling
psychiatric disease in animals has proven enormously challenging, because
etiology is often obscure and symptomatology is often difficult to translate to
non-verbal species. We believe that the development of valid models
hinges on a sufficient degree of understanding of pathophysiology to ensure
validity when translating to animals. Fortunately, studies at Yale and elsewhere are beginning to
produce such understanding in the case of Tourette syndrome. We are using
genetic methods to produce putative models of Tourette syndrome based both on
post-mortem findings (in collaboration with Flora Vaccarino) and on genetic
insights (in collaboration with Matt State). These animals are then being
tested in a variety of behavioral assays to assess their recapitulation of
Tourette syndrome phenomenology, explore secondary and tertiary consequences of
the initial manipulations, and investigate the response to both established and
novel medications.

A FOCUS ON
TRANSLATIONAL RESEARCH: NEW MEDICATIONS FOR OBSESSIVE-COMPULSIVE DISORDER (OCD). The final focus of the Pittenger
laboratory is also translational. Dr. Pittenger is Director of the Yale
OCD Research Clinic, where he has found glutamate-modulating medications to be
of potential benefit in the treatment of patients with obsessive-compulsive
disorder (a condition in which basal ganglia dysfunction is implicated).
We are examining the behavioral and molecular effects of such glutamate-modulating
drugs in animals, to better understand their role in patients with this and
related conditions. As new animal models of
disorders of the basal ganglia, like OCD, become available, we hope to use this
translational approach to advance our understanding both of the normal role of
the basal ganglia in behavior and its perturbation in disease, and to develop
new generations of therapeutics for the psychiatric population.

Lee, A.S., Duman, R.S., and Pittenger, C. (2008). Bidirectional competition between striatum and hippocampus during learning: a double dissociation. Proceedings of the National Academy of Sciences, USA, 105:17163-8.